Rahaman S Ohidar, Lennon David J, Febbraio Maria, Podrez Evgeny A, Hazen Stanley L, Silverstein Roy L
Department of Cell Biology, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio 44195, USA.
Cell Metab. 2006 Sep;4(3):211-21. doi: 10.1016/j.cmet.2006.06.007.
Accumulation of macrophage foam cells in atherosclerotic blood vessel intima is a critical component of atherogenesis mediated by scavenger receptor-dependent internalization of oxidized LDL. We demonstrated by coimmunoprecipitation and pull-down assays that the macrophage scavenger receptor CD36 associates with a signaling complex containing Lyn and MEKK2. The MAP kinases JNK1 and JNK2 were specifically phosphorylated in macrophages exposed to oxLDL. Using cells isolated from SRA, TLR2, or CD36 null mice, and phospholipid ligands specific for either SRA or CD36, we showed that JNK activation was mediated by CD36. Both foam cell formation and activation of JNK2 in hyperlipidemic mice were diminished in the absence of CD36. Furthermore, inhibition of Src or JNK blocked oxLDL uptake and inhibited foam cell formation in vitro and in vivo. These findings show that a specific CD36-dependent signaling pathway initiated by oxLDL is necessary for foam cell formation and identify potential targets for antiatherosclerosis therapy.
巨噬细胞泡沫细胞在动脉粥样硬化血管内膜中的积聚是由清道夫受体依赖性内化氧化型低密度脂蛋白（oxLDL）介导的动脉粥样硬化形成的关键组成部分。我们通过免疫共沉淀和下拉实验证明，巨噬细胞清道夫受体CD36与包含Lyn和MEKK2的信号复合物相关联。在暴露于oxLDL的巨噬细胞中，丝裂原活化蛋白激酶JNK1和JNK2被特异性磷酸化。使用从SRA、TLR2或CD36基因敲除小鼠分离的细胞，以及对SRA或CD36特异的磷脂配体，我们表明JNK激活是由CD36介导的。在缺乏CD36的情况下，高脂血症小鼠的泡沫细胞形成和JNK2激活均减少。此外，抑制Src或JNK可阻断oxLDL摄取，并在体外和体内抑制泡沫细胞形成。这些发现表明，由oxLDL启动的特定CD36依赖性信号通路对于泡沫细胞形成是必需的，并确定了抗动脉粥样硬化治疗的潜在靶点。
